AstraZeneca announced that the Committee for Medicinal Products for Human Use (CHMP), the scientific advisory committee of the European Medicines Agency (EMEA), has issued a positive opinion supporting approval of the targeted oral anti-cancer drug, IRESSA (gefitinib).

The CHMP has recommended the approval of IRESSA for adults with locally advanced or metastatic non-small cell lung cancer (NSCLC) with activating mutations of EGFR-TK (epidermal growth factor receptor-tyrosine kinase), in all lines of therapy.

IRESSA acts by inhibiting the tyrosine kinase enzyme in the EGFR, thus blocking the transmission of signals involved in the growth and spread of tumours. A mutation in the EGFR is a characteristic occurring in 10-15% of lung cancers in Europe , and studies have shown that these types of tumours are particularly sensitive to IRESSA. ; There are approximately 106,000 new cases of advanced lung cancer in Europe (top 5 countries) per year. ;

Anders Ekblom, Executive Vice President for Development at AstraZeneca, said: "Today's positive CHMP opinion on IRESSA is an important step towards addressing the great unmet medical need of lung cancer patients in Europe, and supports AstraZeneca's personalised healthcare strategy to develop the right medicine for the right patient. If IRESSA is approved, for the first time patients with these types of EGFR positive tumours will have a better alternative to chemotherapy as a first-line treatment."

The CHMP opinion is based on a submission package including two pivotal Phase III studies, IPASS and INTEREST.

The IPASS study exceeded its primary objective, demonstrating superior progression-free survival (PFS, the time a patient lives without their cancer progressing), greater objective response rate (ORR, tumour shrinkage), improved tolerability and significant quality of life benefits for IRESSA compared to carboplatin/paclitaxel doublet chemotherapy in clinically selected first-line patients in Asia. However, the treatment effect was not constant over time, with the probability of being progression-free in favour of carboplatin/paclitaxel in the first 6 months and in favour of IRESSA in the following 16 months. This was likely due to the different effect of IRESSA in subgroups defined by EGFR tumour mutation status. PFS was significantly longer for IRESSA than doublet chemotherapy in patients with EGFR mutation positive tumours, and significantly longer for doublet chemotherapy than IRESSA in patients with EGFR mutation negative tumours.ii

The INTEREST study met its primary objective, demonstrating equivalent overall survival (OS) and significant quality of life benefits for IRESSA compared to standard chemotherapy (docetaxel) in the pre-treated setting. Pre-planned sub-group analyses showed a significant improvement in PFS and ORR for IRESSA over docetaxel in patients with EGFR mutation positive tumours.

AstraZeneca will be required to conduct a Follow-up Measure Study, to generate further data in a Caucasian NSCLC patient population. AstraZeneca is in discussion with the CHMP to finalise the study design and endpoints.

The CHMP positive opinion is now referred for final action to the European Commission, which grants marketing approval in the European Union.

IRESSA is already an established therapy for pre-treated NSCLC in the Asia-Pacific region, where AstraZeneca is in consultation with regulatory authorities to discuss the potential use of IRESSA in first-line therapy.

Notes

In 2005, AstraZeneca withdrew its EU marketing authorisation application for IRESSA following data from the Phase III international ISEL study in pre-treated patients not eligible for further chemotherapy. ISEL did not meet its primary objective of a statistically significant improvement in OS for IRESSA compared to placebo, but did confirm a number of important clinical benefits for IRESSA including tumour shrinkage and a significant improvement in time to treatment failure. The refractory* nature of the ISEL population is the most likely explanation for the magnitude of the survival improvement with IRESSA compared to placebo not reaching statistical significance.

* Patients whose tumours had grown during or soon after receiving prior chemotherapy

Following delivery of the INTEREST data, AstraZeneca submitted a new regulatory package to the EMEA in May 2008; the IPASS data were added to the submission package when they became available in Q3 2008.

There is a rolling programme of approvals and licence updates for IRESSA around the world in a broad second-line population based on data from the INTEREST study.

About IRESSA

- Mode of Action: IRESSA is an EGFR-TKI (epidermal growth factor receptor-tyrosine kinase inhibitor), which targets and blocks the activity of the EGFR-TK, an enzyme that regulates intracellular signalling pathways implicated in cancer cell proliferation and survival. Growth factor signalling has been identified as a key driver of tumour growth and spread in a wide range of cancers

- IRESSA (250 mg) is a once-daily oral therapy

- IRESSA is licensed in 36 countries for the treatment of patients with locally advanced or metastatic NSCLC who have previously received chemotherapy

- IRESSA has a well-established, generally well-tolerated side effect profile and is not typically associated with the cytotoxic side-effects commonly seen with chemotherapy. The most commonly seen side-effects of IRESSA are mild-to-moderate rash and diarrhoea. ; ;

- To date, the number of patients who have taken IRESSA is over 300,000 and the maximum time a patient has remained on IRESSA therapy is in excess of eight years.

About the INTEREST and IPASS studies

The INTEREST (IRESSA Non-small-cell lung cancer Trial Evaluating REsponse and Survival against Taxotere) study was a randomised, open-label, parallel-group, Phase III trial evaluating survival with IRESSA versus docetaxel in 1,466 patients with locally advanced or metastatic recurrent NSCLC who had previously received platinum-based chemotherapy. The primary endpoint of INTEREST was OS, with the objective of demonstrating that IRESSA was non-inferior to docetaxel chemotherapy.

IPASS (IRESSA Pan-ASia Study) was an open label, randomised, parallel-group study that assessed the efficacy, safety and tolerability of IRESSA versus carboplatin/paclitaxel as first-line treatment in a clinically selected population of patients from Asia. The primary endpoint of IPASS was PFS (the length of time a patient lives without their tumour progressing), with the objective of demonstrating that IRESSA was non-inferior to carboplatin/paclitaxel doublet chemotherapy.

The study enrolled 1,217 patients in Asia with advanced NSCLC who had not received prior chemotherapy for advanced disease, whose tumours were of adenocarcinoma histology and who had either never smoked, or were former light smokers (ceased smoking at least 15 years ago and